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Outcome of APL patients after ATO-based treatment
Another positive finding is that none of the patients developed a secondary malignancy after ATO/ATRA, com- pared to 2% after chemotherapy,26 representing a major improvement in APL treatment, although we acknowledge that the median follow-up time of our cohort is relatively short. However, the reported latency period between the diagnosis of APL and the development of a secondary malignancy of 6.6 months (range, 3.8-7.6 months) as report- ed by Pagano et al. on behalf of the Gruppo Italiano Malattie Ematologiche dell'Adulto argues strongly for a true lower incidence after ATO/ATRA.27 The low relapse rate after ATO-based therapy in our cohort is in line with other reports.2,3,28
Confirming our previously published data,29 ATO/ATRA was also effective in elderly patients, although age above 70 years was associated with a shorter overall survival and higher cumulative incidence of death in complete remission in comparison with those outcomes in younger patients. Nonetheless, ATO/ATRA should not be withheld in older patients, particularly in light of its high efficacy and safety profile.
The toxicity profiles were comparable to those previ- ously published.2,3 The serious adverse events were main- ly infections and elevation of liver enzymes. Hepatic tox- icity has frequently been reported in studies of ATO, par- ticularly in terms of increased liver enzymes.2,3,30 Although frequent, this complication is usually reversible and suc- cessfully managed with temporary discontinuation of ATO.31 Neurological toxicity, mainly consisting of periph- eral neuropathy, has also been reported.2,3,30 This side effect is usually managed with temporary drug discontin- uation.31 QTc prolongation is another common side effect of ATO. It can lead to torsade-de-pointes-type ventricular arrhythmia, which is potentially fatal.2 However, the reported rate of QTc prolongation was lower than previ- ously published,2-4 as was the rate of differentiation syn- drome,2-4 although the data might be biased due to incom- plete reporting. In our series, most of the patients recov- ered from their serious adverse events, although the out- come was fatal in eight cases.
An unresolved issue is whether or not central nervous sys- tem prophylaxis is needed in APL. Pharmacodynamic stud- ies of plasma levels indicated that about one third of ATO crosses the blood–brain barrier, which suggests that a suffi- cient amount of the drug is available on site to prevent dis- ease recurrence.32 In addition, no ATO accumulation or delayed toxicity was observed in patients followed up for over 10 years.34,35 However, none of our patients was report- ed to have central nervous system involvement at diagnosis.
Regarding biological characteristics, additional cytoge- netic abnormalities were present in 28% of the patients, most frequently t(15;17) within a complex karyotype or trisomy 8, which is in line with published data.35,36 Although data were limited to a small number of patients, FLT3-ITD mutations were less frequent in our cohort than in published data (31%).37 To date, there are still con- flicting data regarding the impact of additional chromoso- mal or genetic abnormalities on outcome in APL patients.38-46 In our large cohort, neither the presence of additional cytogenetic abnormalities nor FLT3-ITD had an impact on overall survival, suggesting that ATO/ATRA may abrogate the negative prognostic impact of FLT3- ITD.46 The latter issue, however, should be interpreted with caution given the limited availability of data on FLT3 mutational status in our cohort.
In conclusion, our real-life data showed excellent and sus- tained response rates after ATO/ATRA for first-line treat- ment of APL, confirming published results from the AP0406 trial.2,3 Compared to reported historical data, the induction death rate was extremely low despite a high bleeding/hem- orrhage rate at diagnosis, probably attributable to improved supportive care and awareness of APL as a medical emer- gency, but also to early treatment with ATO/ATRA itself. Our results confirm the efficiency and sustainability of ATO/ATRA in the primary management of adults with low-/intermediate-risk APL in the real-life setting, irrespec- tiveoftheirage.
Disclosures
UP has received research support from TEVA. CT is chief exec- utive officer and co-owner of AgenDix GmbH. All other authors declare that they have no conflicts of interest.
Contributions
SK and RFS were responsible for the concept of this paper, con- tributed to the literature search and data collection, analyzed and interpreted data, and wrote the manuscript. UP and LA designed the registry, contributed patients, interpreted data and critically revised the manuscript. DL, MC, KSG, FS, AB, KS-E, PP, YH, RR, ER, FC, SWK, WEA, SR, RN, CB, MG, EJ, PC, KK, CO, TB, CS, AA, VK, MW, MdW, DN, CB, CS, JA, AA, SH, AK, AR, MG, CW, KS, WH, CM-T, CR, HS, MB, CDB, EL, and PF contributed patients and critically revised the manuscript. CT performed research and critically revised the manuscript. All authors reviewed and approved the final manuscript.
Acknowledgments
We acknowledge publication support from Leipzig University.
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